Background: Pancreatitis is the most frequent complication of endoscopic retrograde cholangiopancreatography (ERCP), accounting for substantial morbidity, occasional mortality, and increased health care expenditures. Until recently, the only effective method of preventing post-ERCP pancreatitis (PEP) had been prophylactic pancreatic stent placement (PSP), an intervention that is costly, time consuming, and technically challenging. Further, attempting to place a stent can be dangerous because failure of PSP actually increases the risk of pancreatitis above baseline. We recently reported the results of a large-scale randomized controlled trial demonstrating that rectal indomethacin, a non-steroidal anti-inflammatory drug, reduced the risk of pancreatitis after ERCP in high-risk patients, most of whom (>80%) had received a pancreatic stent. Secondary analysis of this RCT suggested that subjects who received indomethacin alone were less likely to develop PEP than those who received a pancreatic stent alone or the combination of indomethacin and stent, even after adjusting for underlying differences in subject risk. If indomethacin were to obviate the need for PSP, major clinical and cost benefits in ERCP practice could be realized. Objective: To develop all the necessary elements to conduct a multi-center clinical study evaluating whether indomethacin can replace PSP for preventing PEP in high-risk patients. Methods: We are proposing a comparative effectiveness multi-center non-inferiority study of rectal indomethacin alone vs. the combination of rectal indomethacin and prophylactic pancreatic stent placement for the prevention of post-ERCP pancreatitis in high-risk patients. One thousand and eighty subjects at elevated risk for PEP who would normally receive a pancreatic stent for prophylaxis will be randomized to indomethacin alone or the combination of indomethacin and PSP. The proportion of patients developing PEP and moderate- severe PEP will be compared. The aim of the U34 funding period is to develop, at six clinical sites, the necessary study infrastructure, research plan, database, and scientific, logistic, and regulatory documents to complete a large-volume, multi-center, comparative effectiveness study comparing indomethacin alone vs. the combination of rectal indomethacin and prophylactic pancreatic stent placement. In addition, we aim to establish a high standard, quality-assured central repository for biological specimens acquired from study subjects on which future translational studies of PEP prevention can be conducted.